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Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 15, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp003
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Cardiac Chymase Converts rat proAngiotensin-12 (PA12) to Angiotensin II: Effects of PA12 upon cardiac hemodynamics

Hamish C.G. Prossera,b,*, Malcolm E. Forstera, A. Mark Richardsb and Chris J. Pembertonb

a School of Biological Sciences, University of Canterbury, Christchurch, New Zealand
b Christchurch Cardioendocrine Research Group, Department of Medicine, University of Otago, Christchurch, New Zealand

* Correspondence to Hamish Prosser, School of Biological Sciences, University of Canterbury, PO Box 4800, Christchurch, New Zealand. hcp17{at}student.canterbury.ac.nz Phone 0064 3 364 0848; Fax 0064 3 3640818

Aims: The aim of this study was to observe the direct physiological and biochemical cardiac effects in response to a newly identified putative component of the renin-angiotensin system (RAS), proangiotensin-12 (PA12); and investigate whether PA12 can serve as a substrate for Angiotensin II (AngII) generation.

Methods: The direct cardiac actions of PA12 and its role as a substrate for chymase-dependent AngII generation were investigated in Sprague-Dawley rats using an isolated heart model of cardiac ischemia reperfusion injury.

Results: PA12 potently constricted coronary arteries with no significant effect on left ventricular contractility. PA12 impaired recovery from global ischemia, maintaining coronary constriction and markedly increasing release of creatine kinase (CK) and troponin I (TnI), indicating greater myocardial injury. Analysis of perfusate collected after transcardiac passage revealed a marked increase in AngII production from hearts infused with PA12. Cardiac AngII production was not blocked by angiotensin-converting enzyme inhibitors, whereas inhibition of chymase with chymostatin significantly reduced AngII production and attenuated PA12-induced vasoconstriction and myocardial damage following ischemia. Furthermore, Angiotensin II type 1 receptor (AT1R) blockade abolished PA12 activity. In vitro, PA12 was efficiently and precisely converted to AngII as assessed on reverse phase-high performance liquid chromatography (RP-HPLC) coupled to tandem Mass Spectrometry. This conversion was blocked by chymostatin.

Conclusion: PA12 may act as a circulating substrate for cardiac chymase-mediated AngII production, in contrast to ACE-mediated AngII production from AngI.

KEYWORDS proAngiotensin-12; Langendorff isolated rat heart; Ischemia-reperfusion injury; Cardiac Angiotensin II production; Chymase

Time for primary review: 41 Days


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